JP2002517491A - Benzo (b) thiepin-1,1-dioxide derivative, process for producing the same, medicament containing these compounds and use thereof - Google Patents

Abstract

(57) Abstract: The present invention relates to substituted benzo (b) thiepine-1,1-dioxide derivatives and acid addition salts thereof. The present invention relates to compounds of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z are as described herein, physiologically acceptable salts, derivatives having a physiological function, and derivatives thereof. It relates to a manufacturing method. This compound is suitable, for example, as a hypolipidemic agent. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to substituted benzo (b) thiepin-1,1-dioxide derivatives, their physiologically acceptable salts and derivatives having physiological functions. Benzo (b) thiepin-1,1-dioxide derivatives and their use in the treatment of hyperlipidemia and arteriosclerosis and hypercholesterolemia have already been described (PCT Application No. PCT / US 97/04076). , Publication No. WO 97/3
3882).

[0002] The invention was based on the object of making available other compounds with hypolipidemic effects which could be applied in therapy. In particular, the aim was to find new compounds which, even at lower doses, caused a greater elimination of bile acids in the stool compared to certain compounds described in the prior art. Compared to the compounds described in the prior art,
Those that reduced the dose of the ED ₂₀₀ value by at least a factor of 5 were particularly preferred.

Accordingly, the present invention provides a compound of formula I

Embedded image (Wherein, R ¹ is methyl, ethyl, propyl, butyl, R ² is H, OH, NH ₂ , NH— (C ₁ -C ₆ ) -alkyl, R ³ is an amino acid group, a diamino acid group , triamino acid, a tetrapeptide amino acid groups, in some cases the amino acid groups, diamino groups are monosubstituted or polysubstituted triamino acid or tetra amino acid group by an amino acid protective group, R ⁴ is methyl, ethyl, propyl , butyl, R ⁵ is methyl, ethyl, propyl, butyl, Z is _{- (C = O) n -C} 0 -C 16 - alkyl, _{- (C = O) n -C} 0 -C 16 - alkyl -NH -, - (C = O ) n -C 0 -C 16 - alkyl -O -, - (C = O ) n -C 1 -C 16 - alkyl - (C = O) _m, a covalent bond N is 0 or 1; m is 0 or 1); It relates to pharmaceutically acceptable salts and physiologically functional derivatives.

Preferred compounds of the formula I have the meaning of one or more groups, wherein R ¹ is ethyl, propyl, butyl and R ² is H, OH, NH ₂ , NH— (C ₁ -C ₆ ) - alkyl, R ³ is an amino acid group, diamino acid groups, in some cases the amino acid groups are monosubstituted or polysubstituted diamino acid group by an amino acid protective group, R ⁴ is methyl, ethyl, propyl, butyl, R ⁵ is methyl, ethyl, propyl, butyl, Z is _{- (C = O) n -C} 0 -C 16 - alkyl, _{- (C = O) n -C} 0 -C 16 - alkyl -NH -, - (C = O ) n -C 0 -C 16 - alkyl -O -, - (C = O ) n -C 1 -C 16 - alkyl - (C = O) _m, a covalent bond Wherein n is 0 or 1, m is 0 or 1, and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of the formula I have the meaning of one or more groups, wherein R ¹ is ethyl, butyl, R ² is OH, R ³ is a diamino acid group, optionally Wherein the diamino acid group is mono- or poly-substituted by an amino acid protecting group, R ⁴ is methyl, R ⁵ is methyl, Z is — (C ＝ O) —C ₀ -C ₄ -alkyl, covalent bond And pharmaceutically acceptable salts thereof.

[0006] Since a pharmaceutically acceptable salt is more water soluble than the starting compound or the base compound, the salt is particularly suitable for pharmaceutical applications. The salt must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of compounds of the present invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids, and, for example, acetic acid, benzenesulfone Acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothioic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, Salts of organic acids such as tartaric acid and trifluoroacetic acid. It is particularly preferred to use chloride salts for the drug. Suitable pharmaceutically acceptable basic salts are ammonium, alkali metal (eg, sodium and potassium) and alkaline earth metal (eg, magnesium and calcium) salts.

[0007] Salts having pharmaceutically unacceptable anions are also useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for non-therapeutic uses, eg, in vitro applications. Are included in the scope of the present invention.

As used herein, the term “physiologically functional derivative” refers to any derivative of a physiologically acceptable compound according to the present invention, for example, when administered to a mammal such as a human, for example. Esters capable of producing (directly or indirectly) such compounds or their active metabolites are indicated.

Another aspect of the present invention is a prodrug of a compound according to the present invention. Such prodrugs can be metabolized in vivo to produce a compound of the present invention. This prodrug is active or inactive by itself. The compounds of the present invention may exist in various polymorphous forms, for example as amorphous and crystalline polymorphs. All polymorphs of the compounds according to the invention are within the scope of the invention and are another aspect of the invention.

In the following, all references to “compounds of the formula (I)” refer to the compounds of the formula (I) above, and also to the salts, solvates and physiologically functional derivatives thereof as described above. . The amount of the compound of formula (I) required to obtain the desired biological effect depends on many factors,
For example, it depends on the particular compound chosen, the intended use, the mode of administration and the clinical condition of the patient. In general, the daily dose is 0.1-kg / kg body weight.
100 mg (typically 0.1 to 50 mg), for example in the range of 0.1 to 10 mg / kg / day. Tablets or capsules may contain, for example, from 0.01 to 100 mg, typically from 0.02 to
May contain 50 mg. In the case of pharmaceutically acceptable salts, the above weight data relates to the weight of benzo (b) thiepine derived from the salt. For the prophylaxis or treatment of the above mentioned conditions, the compounds of formula (I) may be used by themselves, but are preferably present in the form of a pharmaceutical composition with acceptable excipients. It goes without saying that the excipient must be acceptable in the sense that it is compatible with the other components of the composition and is not deleterious to the health of the patient. Excipients may be solid or liquid or both, and are preferably formulated with the compound as individual dosage forms, for example as tablets, which may contain between 0.05 and 95% by weight of active compound. Other pharmaceutically active substances may also be present, including other compounds of formula (I). Pharmaceutical compositions according to the invention can be manufactured by one of the known pharmaceutical methods consisting essentially of mixing the components with pharmaceutically acceptable excipients and / or auxiliaries.

Although the pharmaceutical compositions of the present invention are compositions suitable for oral (eg, sublingual) administration, the most preferred method of administration will, in each individual case, depend on the nature and severity of the condition to be treated. It depends in each case on the type of compound of formula (I) used. Coated and coated delayed release formulations are also within the scope of the invention. Acid resistant and enteric formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Pharmaceutical compounds suitable for oral administration may be present in discrete units, such as, for example, capsules, cachets, troches or tablets, each of which contains a specific amount of a compound of formula (I). The compounds are contained as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. As already mentioned, these compositions may be prepared in any suitable pharmaceutical manner, comprising the step of contacting the active compound with an excipient, which may contain one or more additional components. Can be manufactured. In general, the compositions are prepared by uniformly and intimately mixing the active compound with liquid and / or finely divided solid excipients, after which the product is shaped if necessary. Thus, for example, a tablet can be prepared by compressing or molding a powder or granules of the compound, if appropriate with one or more additional ingredients. Compressed tablets are suitable, for example, by mixing the compound in a flowable form, such as a powder or granules, with a binder, lubricant, inert diluent and / or one or more surfactants / dispersants as appropriate. Can be manufactured by tableting in a suitable machine. Molded tablets may be made by molding in a suitable machine, the finely divided compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for oral (sublingual) administration include lozenges containing a compound of formula (I) with flavoring agents, conventionally sucrose and acacia or tragacanth, and gelatin and glycerol or sucrose and arabic. Some tablets contain the compound in an inert base such as a rubber.

The invention further relates to both the isomer mixtures of the formula I and the pure stereoisomers of the formula I, as well as the diastereoisomeric mixtures and the pure diastereoisomers of the formula I. Separation of the mixture is performed by chromatography.

Preferred racemic and enantiomerically pure compounds of formula I have the following structures:

Embedded image It has.

Amino acids or amino acid residues mean, for example, the stereoisomeric forms of the following compounds, ie D- or L-form. Alanine glycine proline cysteine histidine glutamine aspartic acid isoleucine arginine glutamic acid lysine serine phenylalanine leucine threonine tryptophan methionine valine tyrosine asparagine 2-aminoadipic acid 2-aminoisobutyric acid 3-aminoadipic acid 3-aminoisobutyric acid beta-araminic acid beta-aranin 2,4-diaminoisobutyric acid 4-aminobutyric acid desmosin piperidic acid 2,2-diaminopimelic acid 6-aminocaproic acid 2,3-diaminopropionic acid 2-aminoheptanoic acid N-ethylglycine 2- (2-thienyl) glycine 3- ( 2-thienyl) alanine penicylamine sarcosine N-ethylasparagine N-methylisoleucine hydroxylysine 6-N -Methyllysine allo-hydroxylysine N-methylvaline 3-hydroxyproline norvaline 4-hydroxyproline norleucine isodesmodin ornithine arrow isoleucine N-methylglycine

Abbreviations for amino acids are commonly used in conventional notation (Schroeder, Luebke, The P
eptides, Volume 1, New York, 1965, pp. 22-23; Houben-Weyl,
Methoden der Organischen Chemie [Methods of Organic Chemistry], XV / 1
And Vol. 2, Stuttgart, 1974). The amino acid pGlu is pyroglitamyl, Nal is 3- (2-naphthyl) alanine, azagly-NH ₂
Is a compound of the formula NH ₂ —HN—CONH ₂ , and D-Asp is D-type aspartic acid. Peptides are acid amides by their chemical nature and degrade to amino acids upon hydrolysis. Di-amino acid residues, tri-amino acid residues and tetra-amino acid residues are understood to mean peptides synthesized from 2 to 4 of the above amino acids.

Suitable protecting groups used for amino acids (eg, TW. Greene, “Protect
ive Groups in Organic Synthesis ”) mainly consists of Arg (Tos), Ar
g (Mts), Arg (Mtr), Arg (PMV), Asp (OBzl), Asp (O
But), Cys (4-MeBzl), Cys (Acm), Cys (SBut), Gl
u (OBzl), Glu (OBut), His (Tos), His (Fmoc), His
(Dnp), His (Trt), Lys (Cl-2), Lys (Boc), Met (O),
Ser (Bzl), Ser (But), Thr (Bzl), Thr (But), Trp (
Mts), Trp (CHO), Tyr (Br-Z), Tyr (Bzl) or Tyr (b
ut).

The amino protecting group used is preferably a benzyloxycarbonyl (Z) group which can be removed by catalytic hydrogenation, 2- (3,
5-dimethyloxyphenyl) prop-2-yloxycarbonyl (Ddz) or trityl (Trt) group and can be removed by a secondary amine 9
-A fluorenylmethyloxycarbonyl (Fmoc) group.

The present invention is directed to a process for preparing a benzo (b) thiepine-1,1-dioxide derivative of Formula I.

Embedded image

An amine of formula II wherein R ¹ , R ² , R ⁴ and R ⁵ have the meaning indicated for formula I,
R ³ and Z are reacted with a compound of formula III having the meanings of formula I, formula I to remove water
And optionally converting the resulting compound of formula I to a physiologically acceptable salt or derivative having a physiological function. If the group R ³ is a mono-amino acid, this group may optionally be further extended stepwise after coupling with an amine of formula II to give a di-, tri- or tetra-amino group. Can also.

The compounds of the formula I and their pharmaceutically acceptable salts and physiologically functional derivatives are ideal medicaments for the treatment of lipid metabolism disorders, in particular hyperlipidemia. Formula I
The compounds of the invention influence serum cholesterol levels and are likewise suitable for the prevention and treatment of arteriosclerosis. The compound can optionally be administered in combination with a statin such as, for example, simvastatin, fluvastatin, paravastatin, cerivastatin, lovastatin or atorvastatin. The pharmacological effects of the compounds according to the invention are confirmed by what has been found below.

Biological testing of the compounds of the present invention was performed by measuring the ED ₂₀₀ excretion.
This study examines the effects of compounds of the present invention on bile acid transport in the ileum and fecal excretion of bile acids in rats after oral administration twice daily. A mixture of diastereoisomers of this compound was tested.

The test was performed as follows. 1) Preparation of test and reference substances The following formulation was used to formulate the aqueous solution: a sufficient volume containing Solutol (= polyethylene glycol 600 hydroxystearate, BASF from Ludwigshafen, Germany, batch No. 1763) Dissolve substance in aqueous solution, final concentration 5%
Of Solutol was present in the aqueous solution. The solution / suspension was administered orally at a dose of 5 ml / kg.

2) Experimental conditions Male Wistar rats (Kastengrund, Hoechst AG, weight range 250-350 g)
Into groups of six each and reverse the rhythm of day and night (darken 4-16 o'clock,
From 16 to 4 o'clock), a standard feed mixture (Altromin, Lage, Germany) was given 10 days before the start of the treatment (day 1). Three days before the start of the experiment (day 0), the animals were divided into groups of four each.

Dividing animals into treatment groups

[Table 1]

3) Progress of the experiment 5 μCi of ¹⁴ C-taurocholate was administered intravenously or subcutaneously per rat (day 0), and then the vehicle was administered at 7-8 and 15-16 on the next day (day 1). Alternatively, test substances were given (1 day treatment). Stool samples for analysis of ¹⁴ C-taurocholate were taken every 24 hours immediately after administration of the morning dose. Feces were weighed and stored at -18 ° C, then suspended in 100 ml of demineralized water and homogenized (Ultra Turrax, Janke & Kunkel, IKA-Werk)
. An aliquot portion (0.5 g) was weighed and placed in a combustion unit (Tri Carb® 307 combustor, Canberra Packard GmbH, Frankfurt am Main, Germany) with a combustion lid (
Combusto Cones, Canberra Packard). ¹⁴ CO ₂ obtained is Carbo-So
Absorbed with rb® (Canberra Packard). Scintillator (Perma-F)
luor Complete Scintillation Cocktail No. 6013187, Packard) was added, followed by the following ¹⁴ C radioactivity measurements by liquid scintillation counting (LSC). Fecal excretion of ¹⁴ C-taurocholic acid was calculated as cumulative radioactivity and / or percentage residual radioactivity (see below).

4) Findings and Measurements ¹⁴ C-TCA in burned aliquots of stool samples taken at 24 hour intervals
Stool excretion is measured and calculated as the "cumulative percentage" of the given radioactivity and the percentage of residual radioactivity (residual radioactivity, ie given radioactivity minus radioactivity already excreted) Expressed as To calculate the dose-response curve, the excretion of ¹⁴ C-taurocholic acid was expressed as a percentage of the corresponding value of the control group (treated with vehicle). The ED _200, ie, the fecal excretion of ¹⁴ C taurocholic acid was compared with that of the control group by 200.
Dose increasing to% is calculated by interpolation from sigmoidal or linear dose-response curves. The calculated ED ₂₀₀ corresponds to a dose that doubles fecal excretion of bile acids.

5) Results Table 1 shows the measured ED ₂₀₀ emissions.

[Table 2]

6) Discussion From the measured data, it is inferred that the compounds of the formula I according to the invention have a 20-fold better effect than the compounds described in the prior art.

The following examples serve to illustrate the invention in more detail without limiting the invention to the products and embodiments presented there. Example 4

Embedded image C ₄₆ H ₇₄ N ₆ O ₉ S (887.20). MS (M + H) ^<+> = 887.5.

Comparative Example from PCT / US97 / 04076

Embedded image

The compounds of the examples and comparative examples were produced as follows (in the production, only the synthesis of diastereoisomers is shown).

Embedded image

Synthesis of compound 6 as a mixture of diastereoisomers 150 mg (0.35 mmol) of 1a / b and 245 mg (6 ml of DMF)
0.55 mmol) of Fmoc-D-Lys (Boc) -OH5 (Fluka)
mg TOTU, 74 mg oxime and 0.5 ml NEM were reacted as in the synthesis of compound 3. 290 mg of 6a / b was obtained as an amorphous solid (94%). TLC
(Ethylene acetate / n-heptane 2: 1). _Rf = 0.6. C ₅₀ H ₆₄ N ₄ O ₈
S (881.15). MS (M + H) ^<+> = 881.5.

Synthesis of Compound 7 as a mixture of diastereoisomers 285 mg (0.32 mmol) of 6a / b were dissolved in 5 ml of DMF. 0.6
After addition of ml of diethylamine, the mixture was left for 30 minutes. A finishing operation was performed in the same manner as in the synthesis of compound 3. 173 mg of 7a / b were obtained as an amorphous solid (
81%). TLC (methylene chloride / methanol, 15: 1). R _f = 0.2
, Starting material 6a / b _Rf = 0.4. _{C 35 H 54 N 4 O 6} S (658.91). MS (M +
H) ⁺ = 659.4.

Synthesis of compound 8 as a mixture of diastereoisomers 168 mg (0.25 mmol) of 7a / b were reacted as in the synthesis of compounds 6 and 7, giving 169 mg of 8a / b as an amorphous solid. (75 over two stages
%). TLC (methylene chloride / methanol, 9: 1). _Rf = 0.3. C ₄₆ H ₇₄ N ₆ O ₉ S (887.20). MS (M + H) ^<+> = 887.5.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 337/08 A61K 37/02 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, I, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV , MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, U.S.A., UZ, VN, YU, ZA, ZW (72) Inventor Alfons Ensen Germany Day 64572 Büttelborn. Birkenweg 4 (72) Inventor Heiner Grombic Germany 65157 Hofheim. Am Lotzenwald 42 (72) Inventor Hubert Heuer Day 55550 Schwabenheim, Germany. Am Sportfeld 74

Claims (11)

[Claims] 1. A compound of the formula I (Wherein, R ¹ is methyl, ethyl, propyl, butyl, R ² is H, OH, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, R ³ is an amino acid group, a diamino acid group , triamino acid, a tetrapeptide amino acid groups, in some cases the amino acid groups, diamino groups are monosubstituted or polysubstituted triamino acid or tetra amino acid group by an amino acid protective group, R ⁴ is methyl, ethyl, propyl , butyl, R ⁵ is methyl, ethyl, propyl, butyl, Z is _{- (C = O) n -C} 0 -C 16 - alkyl, _{- (C = O) n -C} 0 -C 16 - alkyl -NH -, - (C = O ) n -C 0 -C 16 - alkyl -O -, - (C = O ) n -C 1 -C 16 - alkyl - (C = O) _m, a covalent bond N is 0 or 1, and m is 0 or 1), or Pharmaceutically acceptable derivatives of salts and physiological functions. 2. One or more groups wherein R ¹ is ethyl, propyl, butyl, R ² is H, OH, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl; ³ amino groups, a diamino acid radical, optionally amino groups are monosubstituted or polysubstituted diamino acid group by an amino acid protective group, R ⁴ is methyl, ethyl, propyl, butyl, R ⁵ is methyl, ethyl, propyl, butyl, Z is _{- (C = O) n -C} 0 -C 16 - alkyl, _{- (C = O) n -C} 0 -C 16 - alkyl -NH -, - (C = O) _n -C ₀ -C ₁₆ -alkyl-O-,-(C = O) _n -C ₁ -C ₁₆ -alkyl- (C = O) _m , a covalent bond, and n is 0 or 1. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein m is 0 or 1. 3. One or more groups, wherein R ¹ is ethyl, butyl, R ² is OH, R ³ is a diamino acid group, optionally wherein the diamino acid group is protected by an amino acid protecting group. are monosubstituted or polysubstituted, R ⁴ is methyl, R ⁵ is methyl, Z is _{- (C = O) -C 0} -C 4 - alkyl, a covalent bond, according to claim 1 or 2 Or a pharmaceutically acceptable salt thereof. 4. Reaction formula Reacting an amine of formula II wherein R ¹ , R ² , R ⁴ and R ⁵ have the meaning indicated for formula I with a compound of formula III wherein R ³ and Z have the meaning of formula I to remove water A compound of formula I, and optionally converting the obtained compound of formula I to a physiologically acceptable salt or derivative having a physiological function. Of the compounds of formula I of the formula 5. A medicament comprising one or more compounds according to claim 1. 6. A medicament comprising one or more compounds according to claim 1 and one or more statins. 7. The compound according to claim 1, which is used as a medicament for treating a lipid metabolism disorder. 8. One or more compounds according to claim 1, comprising mixing the active compound with a pharmaceutically suitable excipient and bringing the mixture into a form suitable for administration. A method for producing a medicament comprising the above. 9. A method for producing a medicament for treating hyperlipidemia.
Use of the compound according to any one of the above. 10. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for influencing serum cholesterol levels. 11. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for preventing atherosclerotic symptoms.